PHAROS (Prospective Huntington At Risk Observational Study) is a multi-site longitudinal project that aims to gain knowledge about: (1) Huntington's disease (HD) gene-specific clinical precursors and predictors of early manifest disease and their relationship to environmental and genetic modifiers, and (2) the feasibility, psychosocial and ethical considerations in studying a population of adults at high risk for HD who have chosen not to learn of their gene carrier status by predictive DNA testing. Between July 1999 and January 2004, 1001 adults at immediate risk (50:50) for HD consented to participate in PHAROS under conditions that: (1) their blood sample be analyzed for the mutant HD gene, an expanded CAG trinucleotide repeat, and (2) individual results of the CAG analysis never be disclosed to anyone, not even to the research participant. This clinically unaffected cohort at baseline has so far been followed for an average of 4 years to determine if and when disease becomes manifest, as measured by the emergence of the unequivocal motor features of HD ('phenoconversion') and as judged by raters unaware of gene status. We propose extending assessment of the PHAROS cohort through 2009 to accrue sufficient phenoconversion events to address our original research aims and define the shape of the phenoconversion curve. The need to extend study of the PHAROS cohort provides the opportunity to examine markers of DNA and RNA damage, 8-hydroxy-2'deoxyguanosine (8-OH2'dG) and 8-hydroxyguanosine (SOHrG) respectively, which are elevated in the blood of individuals with manifest HD and in some gene carriers who have not yet manifested HD. Analysis of blood and urine samples from consenting research participants will help determine: (1) if 8-OH2'dG and SOHrG are elevated specifically in HD gene carriers, (2) to what extent elevations mark the clinical emergence of HD, and (3) the potential value of these indices of DNA/RNA damage as biomarkers of the state and pathogenic activity of HD. Collectively, extending and completing the longitudinal assessment of the PHAROS cohort and examination of DNA and RNA injury markers will: (1) clarify the rate and characteristics of the early clinical onset of HD, (2) the safety, feasibility, psychosocial and ethical considerations in long-term studies of adults at risk for HD, and (3) the utility of measures of DNA/RNA damage as biomarkers of HD. The knowledge from this research will enable the efficient design and appropriate conduct of clinical trials to delay the onset of illness in individuals who carry the lethal gene causing HD. The knowledge will also inform how persons at high risk to develop a disabling genetic disease deal with lingering uncertainties about their future health and complex choices about their participation in research.